Estrogen-plus-progestin hormone therapy raises the incidence of invasive breast cancer, the percentage of such cancers that have spread to the lymph nodes at excision, cancer-related mortality, and all-cause mortality, according to a report in the Oct. 20 issue of JAMA.
These conclusions from an 11-year follow-up of 15,408 subjects in the Women’s Health Initiative randomized clinical trial are the direct opposite of those reported by most observational studies of the issue, which linked combined hormone therapy with breast cancers that have more favorable characteristics and with longer patient survival.
The new findings likely foretell another substantial decline in the use of postmenopausal hormone therapy and a subsequent decrease in breast cancer incidence, much as the initial reports from the WHI study did, said Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., and his associates.
They undertook the WHI update in part because “the influence of estrogen-plus-progestin on breast cancer mortality has not been addressed in a randomized trial setting.”
The WHI involved 16,608 postmenopausal women randomly assigned to receive either conjugated equine estrogens plus medroxyprogesterone or placebo beginning in 1993. The study was halted early, in 2002, when an interim analysis found evidence of harm with the treatment. Subjects were advised to discontinue the hormone therapy, and the study was extended to 2005-2009, with all but 17% of the original study subjects consenting to participate in a median follow-up of 11 years.
Among study subjects who took active hormone therapy, there were 385 cases of invasive breast cancer during the extended follow-up, a rate of 0.42% per year. Among those who took placebo, there were significantly fewer cases: 293, a rate of 0.34% per year.
In addition, a significantly larger proportion of breast cancers in the hormone therapy group had positive lymph nodes (81, or 24%), compared with the placebo group (43, or 16%).
And significantly more women who took active treatment died of breast cancer, compared with those who took placebo. The 25 deaths in the active-treatment group represent 2.6 per 10,000 women per year. In contrast, the 12 breast cancer deaths in the placebo group represent 1.3 deaths per 10,000 women per year, Dr. Chlebowski and his colleagues said (JAMA 2010;304:1684-92).
All-cause mortality showed a similar effect: there were 51 deaths (5.3 per 10,000 women per year) with hormone therapy, compared with 31 deaths (3.4 per 10,000 women per year) with placebo.
Unlike observational studies, this study showed no evidence that hormone therapy was associated with estrogen-receptor-positive tumors, which carry a more favorable prognosis. Subgroup analyses also showed no differences in breast cancer risks between the two study groups related to patient age, body mass index, or a shorter duration of hormone treatment.
The discrepancies between the findings of this study and those reported in previous observational studies “likely are related to potential confounding in the observational analyses,” the investigators said.
Reproductive hormones, especially progestin, stimulate angiogenesis. The study results suggest that the potent stimulation by hormone therapy may facilitate growth and metastasis of already established cancers. Unless this risk can be mitigated, “the use of combined hormone therapy – other than short-term therapy in women with climacteric symptoms not ameliorated by other therapies – seems unwarranted,” they added.
The Women’s Health Initiative was funded by the National Heart, Lung, and Blood Institute. Dr. Chlebowski reported ties to AstraZeneca, Novartis, Pfizer Inc., and Amgen. His associates reported ties to Procter and Gamble, Wyeth Laboratories (maker of Prempro used in the WHI), Upsher-Smith Laboratories, Meditrina Pharmaceuticals Inc., Merck and Co., Inc., Boehringer Ingelheim, and Organon, as well as serving as legal consultants regarding hormone therapy.